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Phase Ib pharmacokinetic (PK) and pharmacodynamic (PD) study to define the optimal dose for combining the mTOR inhibitor AP23573 with capecitabine (CAPE)
Phase Ib pharmacokinetic (PK) and pharmacodynamic (PD) study to define the optimal dose for combining the mTOR inhibitor AP23573 with capecitabine (CAPE)
- Source :
- Journal of Clinical Oncology. 24:3065-3065
- Publication Year :
- 2006
- Publisher :
- American Society of Clinical Oncology (ASCO), 2006.
-
Abstract
- 3065 Background: AP23573 is a novel mTOR inhibitor with anti-tumor activity in Phase1 and 2 trials. In vitro, AP23573 is at least additive with chemotherapy agents including 5FU. CAPE is activated to 5FU by thymidine phosphorylase which may be highly expressed in tumors and correlates with progression through angiogenic mechanisms controlled by mTOR. Given the potential for a positive interaction, this trial studied the combination of AP23573 and CAPE in adult patients with solid tumors. Methods: Starting doses were: AP23573 25 mg i.v. on Days 1, 8, and 15 of a 28-day cycle, and CAPE 1650 mg/m2 p.o. daily on Days 1–14. Planned PK and PD studies include analysis of plasma VEGF, PBMC, skin, and tumor samples for effects on pathways associated with mTOR and on the metabolism of CAPE and fluoropyrimidines. Dose limiting toxicity (DLT) was defined as: febrile neutropenia; neutrophils 6/L for ≥ 5 days; ≥ Grade 3 (CTC) thrombocytopenia; non-haematological toxicities ≥ Grade 2 (diarrhea, cardiac or renal); or missing two consecutive weekly doses due to any toxicity. Results: 15 patients have been treated. Three dose levels of weekly AP23573 (25, 37.5 and 50 mg) were completed without DLT. Treatment-related toxicity was mostly mild or moderate (≤ grade 2), with mucositis/stomatitis the most frequent. Anti-tumor activity included a partial response in a case of endometrial cancer, and stable disease > 4 months in 3 cases (1 renal, 1 uterine and 1 head & neck cancer). AP23573 did not affect the PK of CAPE or 5FU but a trend toward a decreased exposure to the catabolite 5-FuH2 was apparent in the presence of AP23573. In keeping with this observation, the activity of dihydro-pyridine-dehydrogenase gradually decreased to 60% of that before AP23573. This decrease was not associated with reduced tolerability. Conclusions: The combination of AP23573 with CAPE is safe with initial indications of anti-tumor activity. This is the first description of a feasible combination of an mTOR inhibitor with an anti-metabolite. Additional dose levels of AP23573 (75 mg) and CAPE (1850 mg/m2/day) are ongoing and PK and PD studies are continuing. [Table: see text]
Details
- ISSN :
- 15277755 and 0732183X
- Volume :
- 24
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Oncology
- Accession number :
- edsair.doi...........c46baa30a31e3ede283ce7e42787312c
- Full Text :
- https://doi.org/10.1200/jco.2006.24.18_suppl.3065